title: Progression of BRAF-induced thyroid cancer is associated with epithelial-mesenchymal transition requiring concomitant MAP kinase and TGFβ signaling.
abstract: Mice with thyroid-specific expression of oncogenic BRAF (Tg-Braf) develop papillary thyroid cancers (PTCs) that are locally invasive and have well-defined foci of poorly differentiated thyroid carcinoma (PDTC). To investigate the PTC-PDTC progression, we performed a microarray analysis using RNA from paired samples of PDTC and PTC collected from the same animals by laser capture microdissection. Analysis of eight paired samples revealed a profound deregulation of genes involved in cell adhesion and intracellular junctions, with changes consistent with an epithelial-mesenchymal transition (EMT). This was confirmed by immunohistochemistry, as vimentin expression was increased and E-cadherin lost in PDTC compared with adjacent PTC. Moreover, PDTC stained positively for phospho-Smad2, suggesting a role for transforming growth factor (TGF)β in mediating this process. Accordingly, TGFβ-induced EMT in primary cultures of thyroid cells from Tg-Braf mice, whereas wild-type thyroid cells retained their epithelial features. TGFβ-induced Smad2 phosphorylation, transcriptional activity and induction of EMT required mitogen-activated protein kinase (MAPK) pathway activation in Tg-Braf thyrocytes. Hence, tumor initiation by oncogenic BRAF renders thyroid cells susceptible to TGFβ-induced EMT, through a MAPK-dependent process.
authors.affiliation: Department of Medicine and Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, USA. knaufj@mskcc.org
authors.forename: J A
authors.initials: JA
authors.lastname: Knauf
authors.forename: M A
authors.initials: MA
authors.lastname: Sartor
authors.forename: M
authors.initials: M
authors.lastname: Medvedovic
authors.forename: E
authors.initials: E
authors.lastname: Lundsmith
authors.forename: M
authors.initials: M
authors.lastname: Ryder
authors.forename: M
authors.initials: M
authors.lastname: Salzano
authors.forename: Y E
authors.initials: YE
authors.lastname: Nikiforov
authors.forename: T J
authors.initials: TJ
authors.lastname: Giordano
authors.forename: R A
authors.initials: RA
authors.lastname: Ghossein
authors.forename: J A
authors.initials: JA
authors.lastname: Fagin
mesh_terms: D000818:Animals; D002277:Carcinoma; D002291:Carcinoma, Papillary; D002417:Cattle; D018450:Disease Progression; D004789:Enzyme Activation / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D020869:Gene Expression Profiling; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009928:Organ Specificity; D010766:Phosphorylation / Q000187:drug effects; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism*; D051899:Smad2 Protein / Q000378:metabolism; D000077273:Thyroid Cancer, Papillary; D013961:Thyroid Gland / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020928:Mitogen-Activated Protein Kinases